Headaches, especially in the form of migraine pain are a wide spread malady.
Valproic acid (VPA), also used in antiepileptic therapy, is a drug which was approved for the treatment of migraine and has been utilized in the treatment of epilepsy for the last 25 years with a few side effects. Two major side effects being teratogenicity and hepatotoxicity, have been associated with valproate therapy.
In humans, valpromide (VPD), which is also used as an anticonvulsant agent, is a prodrug of valproic acid (VPA). It was found to be more potent than VPA though it exerted more significant sedative side effects (Loscher W. and Nau H. (1985) Neuropharmacology 24: 427-435).
Isomers of VPD, such as valnoctamide (VCD-valmethamide or 2-ethyl-3-methyl pentanamide), were found to be more potent than valproic acid as anticonvulsants (Haj-Yehia A. and Bialer M. (1989) Pharm Res 6:683-9). Stereoselectivity has been shown in pharmacokinetics in man for an amide of an aliphatic short-chain fatty acid such as valnoctamide (VCD) (Barel S., Yagen B., Schurig V., Soback S., Pisani F., Perucca E. and Bialer M. (1997) Clin. Pharmacol. and Therap. 61 (4): 442-449). This work demonstrated that VCD pharmacokinetics (PK) in humans is stereoselective, with one isomer exhibiting a much higher clearance and a shorter half-life compared with the other three stereoisomers.
The present invention relates to the stereoisomers of PIA and of PID and to their isomers (such as VPD and VCA) for use in treatment of neurological and psychotic disorders, and affective disorders and to treat pain, such as head aches. Although VPA and VPD analogues (such as VCA and VCD) were implicated in the treatment of epilepsy, there is no evidence that they in their racemic form or their individual stereoisomers are active in the treatment of neurological and psychotic disorders, affective disorders and pain.